The patent literature describes several different polymorphs of 2-[4-[(methylamino)-carbonyl]-1H-pyrazol-1-yl]adenosine of formula I.
PCT application WO 2008/143667 describes polymorphs A, B, C, and the amorphous form. Polymorph A is prepared by crystallization of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine from protic solvents or their mixtures with water (for example ethanol or an ethanol/water mixture) or by crystallization from polar aprotic solvents or their mixtures with water (for example a dimethylsulfoxide/water mixture). Polymorph A is a monohydrate and, contrary to other as yet known polymorphs, it is relatively stable.
Polymorph B is prepared by concentrating 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine dissolved in trifluoroethanol. The preparation of this polymorph is difficult to reproduce and X-RPD shows broad peaks that are difficult to measure.
Polymorph C is prepared by heating of a suspension of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine in acetonitrile at 60° C. for prolonged periods. This polymorph contains variable amount of water and is converted to unstable forms by heating.
The amorphous form is prepared by heating polymorph A to a temperature of 200° C. The amorphous form is unstable and in presence of air humidity it forms variable hydrates.
PCT application WO 2012/149196 describes preparation of polymorph D by a relatively complicated procedure. First, a “cross coupling” reaction of 2-fluoroadenosine with N-methylpyrazol-4-carboxamide in an acetonitrile/dimethylsulfoxide mixture provides crude 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, which is then purified by reverse-phase chromatography using a methanol/water mixture. After concentrating at 150° C. under reduced pressure, polymorph D is obtained as a white solid substance containing variable amounts of water.
It is known that polymorphs of one medicinal substance can have different physico-chemical properties, such as solubility, stability, density, and compressibility. As a result, they can have different pharmacological properties and also different biological availability. Therefore, deep knowledge of polymorphs is required from the authorities carrying out control of drugs, medicinal substances, and diagnostics (U.S. Food and Drug Administration).